Cancer immunoediting is the process whereby the immune system not only recognizes and destroys developing tumors but also shapes tumor immunogenicity. We formulated this hypothesis 7 years ago and we now know that it occurs in three phases-Elimination, Equilibrium and Escape. Although roles for the interferons (IFN) i.e., Type I IFN and IFN? in this process have been recognized for several years, the critical cellular targets of their action that mediate anti-tumor immunity have remained obscure. In this renewal application, we propose to use mice that we generated on a C57BL/6 background that display tissue specific deficits in either Type I IFN- or IFN?-receptor expression to identify the critical IFN responsive cells needed for immune elimination of tumors and to define their mechanisms of action. We will pursue two Specific Aims. Specific Aim I: Identify the cellular targets of Type I IFN critical for sarcoma elimination and define the functional consequences of Type I IFN effects on these cells. We will assess in vivo rejection of transplanted unedited sarcomas in mice lacking IFNAR1 in different cellular compartments paying particular attention to CD8?+ dendritic cells (DC). Concomitantly we will continue our ongoing studies exploring whether Type I IFN sensitivity is required for cross presentation of tumor antigens by CD11c+ cells and the CD8?+ DC subset and define Type I IFN's mechanism of action in the process. We will determine whether all Type I IFN subtypes (including IFN?) display equivalent activity on these cells and then stringently test the validity of our findings by performing primary MCA tumor induction studies on mice with IFNAR1 deficits in cellular compartments that render them incapable of rejecting unedited tumors. Specific Aim II: Identify the cellular targets of IFN? critical for sarcoma elimination and define the functional consequences of IFN? on these cells. We will assess in vivo rejection of transplanted unedited sarcomas in mice lacking IFNGR1 in different cellular compartments paying particular attention to T cells, macrophages and endothelial cells. Using IFN? sensitive and insensitive T cells, macrophages and/or endothelial cells we will then explore in detail how IFN? alters their cellular biology to induce their participation in either (a) development of anti-tumor immune responses or (b) to act as direct mediators of tumor destruction. Ultimately we will stringently test the validity of our findings by performing primary MCA tumor induction studies on mice with IFNAR1 deficits in cellular compartments that render them incapable of rejecting unedited tumors. PUBLIC HEALTH RELEVANCE: This proposal seeks to identify the particular immune cells that must respond to immune hormones known as interferons. Identifying these cells and defining how they function may lead to new therapeutic strategies that use the immune system to fight cancer.